Neurological symptoms (e.g., dysesthesia such as numbness, pain and the like) associated with the chemotherapy of cancer often pose problems in cancer treatments. For example, a large variety of side effects such as nausea (vomiting), hair loss, anorexia, diarrhea, constipation, limb numbness, pain, stomatitis, leucopenia and the like are known as the side effects of anti-cancer agents such as paclitaxel (taxol) and the like. Among these side effects, neurological symptoms (e.g., dysesthesia such as numbness, pain and the like) caused by peripheral nerve disorders lack an effective improving method.
Acute symptoms of such peripheral nerve disorders include muscular pain and neuralgia, and these symptoms accompany numbness and pain in the fingers and toes as the treatment proceeds. When the symptoms become serious, the quality of life (QOL) of patients is markedly degraded as evidenced by difficulty in using fingers skillfully, increased risk of fall by difficulty in walking due to numb toes and the like.
At present, a medicament clinically effective for these neurological symptoms is not available, and therefore, when these neurological symptoms are developed during treatment with anti-cancer agents, either the dosage of the anti-cancer agents is decreased, medication is discontinued, or medication is withdrawn. Even when the treatment is stopped, sequelae of continued neurological symptoms such as numbness and the like often remain.
In view of the above, neurological symptoms (e.g., dysesthesia such as numbness, pain and the like) by peripheral nerve disorders caused by the administration of an anti-cancer agent form a dose limiting factor of various anti-cancer agents, and the development of a therapeutic drug for mitigating these neurological symptoms associated with a treatment with an anti-cancer agent has been desired (non-patent document 1 and non-patent document 2).
While pain plays the most important role for biological defense, it is also well known to bring an invasive severe pain represented by a neuropathic pain, which exceeds the level of its role and unnecessary for the body. The neuropathic pain is a severe pain that continues even after a complete cure of an injured tissue including peripheral and central nervous systems, which includes hyperalgesia in which even a mild pain stimulation is felt as a severe pain, spontaneous pain accompanying uncomfortable dysesthesia, allodynia in which even a light contact stimulation that does not develop a pain in itself causes a pain and the like.
It has long been unclear in which site such neuropathic pain is expressed by what mechanism. However, some neuropathic pain animal models have been developed in recent years, and the elucidation of the onset mechanism thereof is ongoing. The representative models include the spinal cord nerve ligation model by Kim and Chung (non-patent document 3), the sciatic nerve partial ligation model by Seltzer et al. (non-patent document 4), the model with gentle ligation of the sciatic nerve at several sites by Bennett et al. (non-patent document 5), the model with ligation and cleavage of tibial nerve and whole sural nerve, leaving the sural nerve, by Decosterd and Woolf (non-patent document 6) and the like, all of which creates pathology similar to human chronic neuropathic pain by causing peripheral nerve disorders.
It has been clarified by the analysis of these animal models that the development of neuropathic pain includes one caused by changes in the peripheral nerve such as a sustained increase in the sensitivity or spontaneous firing and the like of the peripheral nerve starting from a peripheral nerve disorder (non-patent document 7), and one caused by changes in the spinal cord or highest center (non-patent document 8). The changes in the spinal cord are caused by activation of microglia, and factors such as cytokine and the like produced and liberated from the activated microglia are considered to stimulate secondary neuron and enhance pain sensitivity.
It has been reported, moreover, that incidents similar to those in neuropathic pain model also occur in animal models of neurological symptoms caused by the administration of an anti-cancer agent. That is, by the administration of an anti-cancer agent such as paclitaxel, vinblastine and the like, hyperalgesia occurs along with a peripheral nerve disorder (non-patent document 9), and microglia is activated in the spinal cord (non-patent document 10). From the above, it is considered that the expression mechanism similar to that in neuropathic pain is also involved in the expression of neurological symptoms in human, which is due to peripheral nerve disorders caused by the administration of an anti-cancer agent.
Patent document 1 describes that (i) a compound represented by the formula:
wherein    R is an aliphatic hydrocarbon group optionally having substituent(s), an aromatic hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), a group represented by the formula: —OR1 wherein R1 is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), or a group represented by the formula:
wherein R1b is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), and R1c is the same as or different from R1b, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s),    R0 is a hydrogen atom or an aliphatic hydrocarbon group, or R and    R0 in combination form a bond,    ring A is a cycloalkene substituted by 1 to 4 substituents selected from (1) an aliphatic hydrocarbon group optionally having substituent(s), (2) an aromatic hydrocarbon group optionally having substituent(s), (3) a group represented by the formula: —OR11 wherein R11 is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), and (4) a halogen atom,    Ar is an aromatic hydrocarbon group optionally having substituent(s),    a group represented by the formula:
is a group represented by the formula:
and n is an integer of 1 to 4, and    (ii) a compound represented by the formula:
wherein    Ra is an aliphatic hydrocarbon group optionally having substituent(s), an aromatic hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), a group represented by the formula: —OR1a wherein R1a is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), or a group represented by the formula:
wherein R4a and R5a are the same or different and each is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s),    R0a is a hydrogen atom or an aliphatic hydrocarbon group, or    Ra and R0a in combination form a bond,    Ara is an aromatic hydrocarbon group optionally having substituent(s),a group represented by the formula:
is a group represented by the formula:
and n is an integer of 1 to 4,    a salt thereof and a prodrug thereof have a nitric oxide (NO) production-inhibiting effect and an inhibitory effect on the production of inflammatory cytokines, such as TNF-α, IL-1, IL-6 and the like, and are useful as an agent for the prophylaxis or treatment of diseases including cardiac diseases, autoimmune diseases, inflammatory diseases, central nervous system diseases, infectious diseases, sepsis, septic shock and the like; and
Patent document 2 describes that a compound represented by the formula:
wherein    R1 is an aliphatic hydrocarbon group optionally having substituent(s), an aromatic hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), a group represented by the formula: —OR1a wherein R1a is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), or a group represented by the formula:
wherein R1b and R1c are the same or different and each is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s),    X is methylene, NH, a sulfur atom or an oxygen atom,    Y is methylene optionally having substituent(s) or NH optionally having substituent(s),    ring A is a 5- to 8-membered ring optionally having 1 to 4 substituents selected from the group consisting of (1) an aliphatic hydrocarbon group optionally having substituent(s), (2) an aromatic hydrocarbon group optionally having substituent(s), (3) a group represented by the formula: —OR2 wherein R2 is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s), and (4) a halogen atom,    Ar is an aromatic hydrocarbon group optionally having substituent(s),a group represented by the formula:
is a group represented by the formula:
    m is an integer of 0 to 2,    n is an integer of 1 to 3, and    the total of m and n is 4 or less;    provided that when X is a methylene group, then Y should be a methylene group optionally having substituent(s), a salt thereof and a prodrug thereof    have a nitric oxide (NO) production-inhibiting effect and an inhibitory effect on the production of inflammatory cytokines, such as TNF-α, IL-1, IL-6 and the like, and are useful as an agent for the prophylaxis or treatment of diseases including cardiac diseases, autoimmune diseases, inflammatory diseases, central nervous system diseases, infectious diseases, sepsis, septic shock and the like.
Patent document 11 describes that the compounds described in the above-mentioned patent document 1 and/or patent document 2 have a TLR (particularly, TLR4) signal inhibitory action, and are useful as an agent for suppressing production or expression of a factor selected from IL-2 (Interleukin-2), IL-3, IL-8, IL-10, IL-12, IL-17, MIP-2 (macrophage inflammatory protein-2), KC (keratinocyte derived-chemokine), GM-CSF (granulocyte-macrophage colony-stimulating factor), IFN (interferon)-γ and prostaglandin E2 and the like, and the like.
Patent documents 3-13 describe that the compounds described in the above-mentioned patent document 1 and/or patent document 2 can be used for the treatment of pain.
However, patent documents 1-13 do not describe that the compounds described in the above-mentioned patent document 1 and/or patent document 2 can suppress peripheral nerve disorders induced by anti-cancer agents.